Neurobiology of sleep onset: the Sleep-wake switch

How does sleep happen?
Understanding “The Sleep Switch” Neurobiology
Awake Asleep

Waking Experience
Desynchronized, Aware
REM Sleep
Desynchronized, Unaware
NREM (Deep) Sleep
Synchronized, Unaware
What You Probably Know

Waking Experience
Desynchronized, Aware
REM Sleep
Desynchronized, Unaware
NREM (Deep) Sleep
Synchronized, Unaware
What You Probably Know
But what about the neurons that make
these EEG patterns?

What Are You Talking About?
● What is the “Sleep Switch”?
○ Does it exist?
○ Neural populations involved?
○ How does it work?
● Switching States:
○ Wake => Sleep
○ REM => NREM
● Importance
○ Disorders of “switching”

What is The “Sleep Switch”?
● Systems Theory:
○ Theoretical concept that
sleep and wake are two,
distinct mental states
○ feedback loop with circuits
running in opposite
● The activity of each circuit
inhibits activity from the other
circuit in turn disinhibiting
itself.
● Similar to a “flip-flow
switches” in electronics
● Little to no transitional state:
either on or off.

Good Theory, but so what?
(Rempe, Best, Terman, 2009)
Mathematical models replicate
neuronal activity
Similar feedback loops in
neural populations

Awake
REM
NREM
REM
Awake
Where do Switches Occur?
Here Here Here Here

Awake
REM
NREM
REM
Awake
Where do Switches Occur?
Here Here Here Here
HOWEVER:
Most literature focuses only on this step.
Second, entering REM

The interrelationship of the two halves of the REM switch. The REM-off region is identified by the overlap of inputs
from the orexin neurons and the eVLPO. These neurons in the vlPAG and LPT have a mutually inhibitory interaction
with REM-on GABAergic neurons of the vSLD, but also inhibit REM generator circuitry in the remainder of the SLD and
the PC. Note that cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT–LDT) are REM-
on and may inhibit the LPT (as cholinergic agonists injected in this region cause REM states), but are not directly
inhibited by it, and thus are not part of the mutually inhibitory flip–flop switch. Similarly, serotoninergic dorsal raphe and
noradrenergic locus coeruleus (DRN–LC) neurons activate the REM-off circuitry, and thus monoamine re-uptake
inhibitors, such as antidepressants, can dramatically suppress REM sleep. However, they also are not inhibited directly
by the SLD, and hence are not part of the mutually inhibitory flip–flop switch
Remaining Literature Inconclusive
(Lu, et al. 2006)( de Lecea, Bourgin. 2006)
“A peptide-centric view of the reciprocal interaction model. The original reciprocal
interaction model proposed that monoaminergic REM-off cells inhibit the activity of cholinergic
REM-on neurons in the pontine reticular formation. Different revisions of the model have added
GABAergic inhibition to these reciprocal interactions and modulation of the REM-off component
by the extended VLPO. The discovery of the role of the hypocretins in narcolepsy and stability of
wakefulness suggested that peptides could also play a relevant neuromodulatory role in this
model. In this review we discuss the role of VIP, PACAP and Urotensin II as putative
neuroregulatory elements of REM on neurons.
REM to NREM

The interrelationship of the two halves of the REM switch. The REM-off region is identified by the overlap of inputs
from the orexin neurons and the eVLPO. These neurons in the vlPAG and LPT have a mutually inhibitory interaction
with REM-on GABAergic neurons of the vSLD, but also inhibit REM generator circuitry in the remainder of the SLD and
the PC. Note that cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT–LDT) are REM-
on and may inhibit the LPT (as cholinergic agonists injected in this region cause REM states), but are not directly
inhibited by it, and thus are not part of the mutually inhibitory flip–flop switch. Similarly, serotoninergic dorsal raphe and
noradrenergic locus coeruleus (DRN–LC) neurons activate the REM-off circuitry, and thus monoamine re-uptake
inhibitors, such as antidepressants, can dramatically suppress REM sleep. However, they also are not inhibited directly
by the SLD, and hence are not part of the mutually inhibitory flip–flop switch
(Lu, et al. 2006)( de Lecea, Bourgin. 2006)
“A peptide-centric view of the reciprocal interaction model. The original reciprocal
interaction model proposed that monoaminergic REM-off cells inhibit the activity of cholinergic
REM-on neurons in the pontine reticular formation. Different revisions of the model have added
GABAergic inhibition to these reciprocal interactions and modulation of the REM-off component
by the extended VLPO. The discovery of the role of the hypocretins in narcolepsy and stability of
wakefulness suggested that peptides could also play a relevant neuromodulatory role in this
model. In this review we discuss the role of VIP, PACAP and Urotensin II as putative
neuroregulatory elements of REM on neurons.
REM to NREM
THIS? THIS?
?
Remaining Literature Inconclusive

Sleep to Wake
What Causes the Switch? When?
(Saper et al.2011)

REM to NREM
(Saper et al.2011)

(Saper et al.2011)
The flip-flop switch:
Red = Inhibition
Green = Facilitation
Sleep-Wake
States

“ sleep is an emergent
property of populations of
local neural networks
undergoing state
transitions”
Thus,
(Clinton et al. 2011)

So… Are We Done?
Not even close!

Only SOME of the Key Brain Areas
Name AKA
Locus Cerlus LC
Turbomamalary N. TMN
Ventrolateral Preoptic Area VLPO
Basial Forbrain BF
Supraciasmatic N. SCN
Lateral Hypothalamic Area LHA
Perifornical area PeF
Name AKA
Periaqueductal gray PAG
Parabrachial nucleus PB
Medial Preoptic N. MnPO
Sublaterodorsal Tegmental N. SLD
Ventromedial hypothalamus VMH
Substantia Niagra SN
Ventral Tegmental Area VTA
DorsalMedial Hypothalmus DMH
Cerebral Cortex CC
Precoeruleus PC
Periventricular Hypothalmus? PVH
Dorsal Raphe N. DR
Lateral Dorsal Tegmentum LDT
pedunculopontine Tegmentum PPT
Name AKA

(De Lecue 2015)
What Different Systems Do
Hcrt
DA
Hist
Integrator A
Gatekeper(s) Pacemaker(s)
Effector(s)Facilitator(s) Theta
Facilitator(s) Gamma
Wake
Sleep
5HT
NE
Ach

ACTH
DASN
DAVTA
NAcc
AChLDT
AChPPT
GABA2GABA2
Hist
Hcrt LC
NPY
BF
Sleep-to-Wake Transition
Ca1/3
POMC
/CART
CRF
Utsn
II
(De Lecue 2015)
The Goal: Integrated Model

ACTH
DASN
DAVTA
NAcc
AChLDT
AChPPT
GABA2GABA2
Hist
Hcrt LC
NPY
BF
Ca1/3
POMC
/CART
CRF
Utsn
II
p .80
p .85
p .18
p .09
p .40
p .14
p .39
p .05
p .44
p .68
p .22
p .41
p .73
p .22
p .13
p .36
p .55
p .20
p .06
p .06
p .11
p .02
p .03
p .32
(De Lecue 2015)

Melatonin Interleukins
Ghrelin TNF∂
Leptin
Adosine
Glucose/
BDNF Insulin
ACTH
DASN
DAVTA
NAcc
AChLDT
AChPPT
GABA2GABA2
Hist
Hcrt LC
NPY
BF
Ca1/3
POMC
/CART
CRF
Utsn
II
p .80
p .85
p .18
p .09
p .40
p .14
p .39
p .05
p .44
p .68
p .22
p .41
p .73
p .22
p .13
p .36
p .55
p .20
p .06
p .06
p .11
p .02
p .03
p .32
(De Lecue 2015)

References
Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip–flop switch for
control of rem sleep.
Rempe, Best J, Terman D (2009) A mathematical model of the sleep/wake
cycle.
Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic
control of sleep and wakefulness.
Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and
circadian rhythms.
Phillips A, Robinson P (2008) Sleep deprivation in a quantitative
physiologically based model of the ascending arousal system.
De Lecea. (2015) Presentation at The University Of Toronto, St George
Clinton, J., Davis, C., Zielinski, M., Jewett, K., & Krueger, J. (2011). Biochemical
Regulation of Sleep and Sleep Biomarkers.
de Lecea L. (2012) Hypocretins and the neurobiology of sleep-wake mechanisms

Neurobiology of sleep onset: the Sleep-wake switch

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